Currently up to 50% of HIV infected individuals including those taking antiretroviral therapy have mild neurocognitive disorder. Furthermore, the population living with HIV infection continues to grow and there are now over one million people living with HIV in the US and 42 million around the world. This indicates that persistent HIV associated cognitive impairment is the most common cause of neurocognitive disorder globally. While significant progress has been made in the treatment and outlook with the advent of antiretroviral medication, HNCI remains a significant burden to persons living with HIV infection and to date has no specific therapy. HNCI has been shown to occur during asymptomatic stages of infection, to increase its prevalence as the illness progresses 7 and to persist despite successful immune reconstitution with HAART. Even mild HNCIs have a significant impact on daily functioning. Compared to cognitively intact HIV infected individuals, impaired persons have a lower quality of life , are more likely to be unemployed 8 9 and have difficulty with medication management 10,11 as well as other activities of daily living 11. The impact of HNCI is further complicated by co-factors such as substance misuse and co-infection with hepatitis C, both of which are being recognized as exacerbating cognitive impairment 12,13 . These additive adverse effects emphasize the importance of the relationship between various symptoms experienced and treatment outcomes, which could be translated as the relationship between HNCI and life expectancy. The scientific significance of this investigation is it will identify brain targeted therapy for HIV in the absence of such therapy and when current antiretroviral therapy is not completely effective in the brain. Thus, identification of novel antiviral drugs that have demonstrable ability to suppress brain viral replication and minimize HIV associated neurodegeneration will assist clinicians in tailoring drug regimes to include such agents in order to prevent or treat HNCI. In summary this 12 month phase I project will generate data in a human brain model of the ability of Samaritan molecules to suppress viral replication and prevent HIV associated neurodegeneration, two pathological events that underlie HNCI. The data from this project will then be the foundation for an STTR phase II trial which will expand the testing of the Samaritan molecules to other viral strains in the in vitro human brain aggregate model, evaluation in SIV infected primates and further preclinical studies that are required to proceed with clinical trials in individuals with HNCI. [unreadable] [unreadable] These studies will allow us to test the ability of the Samaritan molecules to suppress viral replication and prevent neurodegeneration by exploiting our human brain aggregate model infected with HIV. At present, only a modest amount of data identifies which antiretroviral agents are the most successful at suppressing viral replication or preventing neurodegeneration despite a growing need for the therapy. Should these studies and the associated development plans prove successful, the Samaritan molecules will be further developed as promising HIV neurodegeneration therapeutics. [unreadable] [unreadable] [unreadable]